Thioperamide, a histamine H3 receptor antagonist, attenuates neuroimmune activation and inflammation in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of unknown cause that gradually affects upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. The histamine H3 receptor (H3R), a presynaptic autoreceptor, regulates histamine release through feedback mechanisms. H3R is highly expressed in neurons and microglia, where it influences inflammatory responses.

METHODS

This study examined the effects of thioperamide, an H3R antagonist, on T cell-mediated immune responses in the SOD1G93A transgenic mouse model of ALS. Mice received daily thioperamide injections (5 mg/kg) for four weeks, beginning at the onset of illness (week 15). Flow cytometry analyzed splenic CD3+ T cells for cytokine and marker expression, including IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, GM-CSF, TGF-β1, and Foxp3. RT-PCR measured mRNA levels in brain tissue.

RESULTS

Results showed that thioperamide significantly decreased CD3+IL-1α+, CD3+IL-6+, CD3+IFN-γ+, CD3+TNF-α+, CD3+IL-17A+, CD3+RORγt+, CD3+iNOS+, and CD3+GM-CSF+ cells in the spleen, while increasing regulatory CD3+TGF-β1+ and CD3+Foxp3+ cells. Similarly, brain tissue showed decreased mRNA levels of IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, and GM-CSF, with higher TGF-β1 and Foxp3 expression.

CONCLUSIONS

These findings suggest that thioperamide helps reestablish immune balance in SOD1G93A mice by influencing both inflammatory and regulatory T cell pathways.